Sabine Meunier

Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization

Dystonia has a wide clinical spectrum from early‐onset generalized to late‐onset sporadic, task‐specific forms. The genetic origin of the former has been clearly established. A critical role of repetitive skilled motor tasks has been put forward for the latter, while underlying vulnerability traits are still being searched for. Using magnetoencephalography, we looked for structural abnormalities reflecting a preexisting dysfunction. We studied finger representations of both hands in the primary sensory cortex, as compared in 23 patients with unilateral task‐specific dystonia and 20 control subjects. A dramatic disorganization of the nondystonic hand representation was found in all patients, and its amount paralleled the severity of the dystonic limb motor impairment. Abnormalities were also observed in the cortex coding the dystonic limb representation, but they were important only in the most severely affected patients. The abnormal cortical finger representations from the nondystonic limb appear to be endophenotypic traits of dystonia. That finger representations from the dystonic limb were almost normal for the less severely affected patients may be due to intrinsic beneficial remapping in reaction against the primary disorder.

Structural abnormalities in the cerebellum and sensorimotor circuit in writer's cramp

Background: Structural abnormalities were detected in bilateral primary sensorimotor areas in writers cramp. Evidence in other primary dystonia, including blepharospasm and cervical dystonia, suggest that structural abnormalities may be observed in other brain areas such as the cerebellum in writers cramp. Objective: To test the hypothesis that structural abnormalities are present along the sensorimotor and cerebellar circuits in patients with writers cramp. Methods: Using voxel-based morphometry, the authors compared the brain structure of 30 right-handed patients with writers cramp with that of 30 healthy control subjects matched for gender, age, and handedness. Results: Gray matter decrease was found in the hand area of the left primary sensorimotor cortex, bilateral thalamus, and cerebellum (height threshold p < 0.01, cluster significant at p < 0.05 corrected for multiple comparisons). Conclusions: These results demonstrate in writers cramp the presence of structural abnormalities in brain structures interconnected within the sensorimotor network including the cerebellum and the cortical representation of the affected hand. These abnormalities may be related to the pathophysiology of writers cramp, questioning the role of the cerebellum, or to maladaptive plasticity in a task-related dystonia.

Convergence of descending and various peripheral inputs onto common propriospinal-like neurones in man.

1. The patterns of excitation and convergence by peripheral afferents on propriospinal‐like neurones projecting to forearm flexor carpi radialis (FCR) motoneurones in human subjects were determined at rest and during various voluntary contractions, using H reflex testing. 2. At rest, the FCR H reflex could be facilitated by mixed nerve (ulnar, musculocutaneous) and cutaneous (afferents from both sides of the hand) inputs. The characteristics of this facilitation (low threshold, long central latency, short duration) were compatible with those of the propriospinal‐like system. Quantitatively this facilitation was rare and weak. 3. Voluntary contraction increased the extent of the propriospinal‐like facilitation of the FCR H reflex. It is shown in the companion paper (Burke, Gracies, Meunier & Pierrot‐Deseilligny, 1992) that this increase results not from a decrease in presynaptic inhibition of afferents to propriospinal‐like neurones, but from increased excitation of these neurones. It is argued that at the onset of contraction this excitation is purely descending in origin, whereas the contraction‐induced afferent discharge is probably the major factor during weak tonic contraction. 4. The distribution of the increased facilitation of the FCR H reflex depended on the muscles involved in the contraction: ulnar nerve‐evoked facilitation was increased much more at the onset of voluntary wrist flexion than voluntary elbow flexion, and vice versa for the musculo‐cutaneous‐induced facilitation. This finding is consistent with the view that there are subsets of propriospinal‐like neurones, specialized with regard to afferent input, and indicates that descending excitation is directed preferentially to the subset of neurones which receives excitatory feedback from the contracting muscle. 5. To investigate the convergence of different afferent inputs onto common neurones the spatial facilitation technique was used. When present the convergence had a threshold and time course compatible with those of the propriospinal‐like system. Convergence was found between the different mixed nerves and between ulnar and superficial radial nerves. 6. The wide convergence found between different inputs onto common neurones and the finding that, during contraction of a given muscle, descending excitation reaches subsets of neurones projecting to motor nuclei of muscles operating at other joints suggest that the propriospinal‐like system would be operative during complex multi‐joint movements.

Non‐monosynaptic transmission of the cortical command for voluntary movement in man.

1. The possibility was investigated that, in man, some of the descending command for tonic voluntary wrist extension is transmitted to extensor motoneurones over a non‐monosynaptic pathway. 2. Stimulation of the cutaneous superficial radial nerve at 3 times perceptual threshold depressed the electromyogram (EMG) of extensor carpi radialis (ECR) and the discharge of single ECR motor units, both with a mean central delay of 4.2 ms. Such stimuli depressed the response to transcranial magnetic stimulation of the motor cortex, but had little effect on the H reflex. 3. The possibility that the relative sparing of the H reflex was due to an alteration in transmission of the afferent volley for the H reflex was excluded. 4. The central latency of the cutaneous‐induced depression of the discharge of single motor units in biceps brachii (C5‐C6) was shorter by about 1 ms than that of the more caudal wrist and finger extensor motor units. This suggests that the locus for the cutaneous‐induced effects was spinal but above the cervical enlargement. 5. The pattern of EMG depression (evoked by superficial radial but not palmar stimuli, in wrist extensors but not wrist flexors) is that previously described for the presumed propriospinal system of human subjects. 6. It is concluded that a significant component of the voluntary command for tonic wrist extension reaches the relevant motoneurone pool via a non‐monosynaptic pathway. It is suggested that the interposed neurones could be C3‐C4 propriospinal neurones.

Pattern of propriospinal‐like excitation to different species of human upper limb motoneurones.

1. The pattern of distribution of non‐monosynaptic (propriospinal‐like) excitation to various motor nuclei (deltoid, extensors and flexors of the elbow, the wrist and the fingers) was investigated. 2. Changes in the firing probability of individual voluntarily activated motor units were studied following conditioning stimuli. Conditioning volleys were evoked by weak electrical stimuli applied to various mixed nerves (circumflex, musculocutaneous, median, radial, ulnar) and to the skin. 3. In all investigated nuclei stimulation of the ‘homonymous’ nerve evoked a peak of increased firing probability with a latency which was 2‐7 ms longer than the monosynaptic Ia latency. The average central delay of the late excitation, measured from monosynaptic latency, seems to depend only on the segmental level of the motor nucleus: the more caudal the nucleus the longer the latency. This strongly suggest a transmission through neurones located above the cervical enlargement, as are C3‐‐C4 propriospinal neurones in the cat. 4. Both group I muscle and cutaneous afferents were shown to contribute to propriospinal‐like excitation. It is argued that a spatial facilitation of the effects evoked by these two inputs might explain why the threshold of late excitation is always below that of the monosynaptic Ia excitation in motoneurones. 5. The pattern of distribution of propriospinal‐like excitation was diffuse: stimulation of each mixed nerve was able to evoke excitation in all investigated motor nuclei. Similarly, stimulation of a given skin field could produce excitation of biceps and wrist flexor and extensor units. 6. Each motor nucleus therefore receives excitation from a multimodal and wide range peripheral input. However, it is argued that what appears as a diffuse pattern might simply reflect connections which are not used in each movement but appropriately selected by higher centres.

Interhemispheric Plasticity in Humans

INTRODUCTION Chronic unimanual motor practice increases the motor output not only in the trained but also in the nonexercised homologous muscle in the opposite limb. We examined the hypothesis that adaptations in motor cortical excitability of the nontrained primary motor cortex (iM1) and in interhemispheric inhibition from the trained to the nontrained M1 mediate this interlimb cross education. METHODS Healthy, young volunteers (n=12) performed 1000 submaximal voluntary contractions (MVC) of the right first dorsal interosseus (FDI) at 80% MVC during 20 sessions. RESULTS Trained FDIs MVC increased 49.9%, and the untrained FDIs MVC increased 28.1%. Although corticospinal excitability in iM1, measured with transcranial magnetic stimulation (TMS) before and after every fifth session, increased 6% at rest, these changes, as those in intracortical inhibition and facilitation, did not correlate with cross education. When weak and strong TMS of iM1 were delivered on a background of a weak and strong muscle contraction, respectively, of the right FDI, excitability of iM1 increased dramatically after 20 sessions. Interhemispheric inhibition decreased 8.9% acutely within sessions and 30.9% chronically during 20 sessions and these chronic reductions progressively became more strongly associated with cross education. There were no changes in force or TMS measures in the trained groups left abductor minimi digiti and there were no changes in the nonexercising control group (n=8). CONCLUSIONS The findings provide the first evidence for plasticity of interhemispheric connections to mediate cross education produced by a simple motor task.

The anatomical basis of dystonia: Current view using neuroimaging

This review will consider the knowledge that neuroimaging studies have provided to the understanding of the anatomy of dystonia. Major advances have occurred in the use of neuroimaging for dystonia in the past 2 decades. At present, the most developed imaging approaches include whole‐brain or region‐specific studies of structural or diffusion changes, functional imaging using fMRI or positron emission tomography (PET), and metabolic imaging using fluorodeoxyglucose PET. These techniques have provided evidence that regions other than the basal ganglia are involved in dystonia. In particular, there is increasing evidence that primary dystonia can be viewed as a circuit disorder, involving the basal ganglia‐thalamo‐cortical and cerebello‐thalamo‐cortical pathways. This suggests that a better understanding of the dysfunction in each region in the network and their interactions are important topics to address. Current views of interpretation of imaging data as cause or consequence of dystonia, and the postmortem correlates of imaging data are presented. The application of imaging as a tool to monitor therapy and its use as an outcome measure will be discussed.

Cerebellar Processing of Sensory Inputs Primes Motor Cortex Plasticity

Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations.

Spinal use-dependent plasticity of synaptic transmission in humans after a single cycling session

The spinal cord is able to express use‐dependent plasticity, as demonstrated in spinalized cats following treadmill training. In humans, spinal use‐dependent plasticity is inferred from modifications in the size of H reflex, which are often more prominent after skilled motor training. Plasticity can develop at synaptic connections between afferent fibres and/or descending tracts and motoneurones or interneurones interposed in the spinal pathways. Here we explore whether skilled training induces a change in synaptic efficacy at the synapse between Ia afferents and soleus (Sol) motoneurones. Synaptic efficacy can be modulated presynaptically through changes of the probability of transmitter release (homosynaptic depression, HD). The frequency‐related depression of the Sol H reflex, thought to reflect HD, was tested at rest, before and after one single skilled (14 subjects) or non‐skilled (9 subjects) cycling training session. Performance improved in both groups but to a larger extent with skilled training, while HD increased immediately after and the day following skilled training in the absence of changes with non‐skilled training. These results support the view that spinal cord function is able to encode a local motor memory.

Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease

OBJECTIVE To test the plasticity of bilateral motor cortices (M1) in treatment-naïve (de novo) Parkinsons disease (PD) patients and its response to single dose of L-DOPA. METHODS Twenty-one de novo PD patients with only unilateral motor symptoms were recruited to eliminate the effects of advanced disease and chronic treatment and were tested with intermittent (n=10) and continuous theta burst stimulation (iTBS and cTBS) (n=11) protocols to induce LTP and LTD-like plasticity on both M1 cortices. They were compared with two groups of 10 each, age-matched, healthy volunteers (HV). Severity of motor signs and effectiveness of TBS were measured bilaterally in the untreated state and after a uniform dose of L-DOPA in all patients. RESULTS iTBS and cTBS induced significant LTP and LTD- like plasticity in M1 of HV. In de novo patients, there was no plasticity in both M1. Acute L-DOPA challenge did not improve plasticity in either M1 cortices, though motor signs of PD improved. There was no correlation of motor signs with M1 plasticity. CONCLUSION The early, severe and bilateral loss of plasticity in M1 in de novo PD patients is a primary disease-related cortical dysfunction. The contrasting L-DOPA response of motor signs and M1 plasticity could arise from differences in neural circuits mediating them or differing effects of acute dopamine replacement on circuits recruited by specific plasticity-induction techniques, particularly in treatment naïve PD. SIGNIFICANCE M1 plasticity defect occurs early in PD and might affect motor learning. Acute vs. chronic dopamine replacement could have different effects on plasticity in PD or in the networks recruited by a specific plasticity induction technique.